Abstract. There are a number of medical conditions that increase the rate of cognitive decline with age as well as the age of onset and severity of Alzheimer's disease (AD) and other dementias. Among these the most significant conditions include those that are associated with acute and chronic pathologies of the kidney. Acute kidney injury (AKI) due to renal ischemia can occur during surgical procedures, kidney transplantation, and heart disease and frequently leads to cognitive problems. Individuals with diabetes are at risk for both chronic kidney disease (CKD) and AD. While CKD is often associated with old age, its relationship with aging and dementias at the molecular level is not well understood. The goal of this application is to use a bioinformatics?based systems biology approach to identify molecular pathways in the brain that are i) associated with and caused by kidney disease and ii) affect brain aging and cognition. These pathways will be validated using chemical biology and transgenic approaches. To accomplish this work, a number of experimental paradigms will be used and integrated. Mouse models of both renal ischemia-reperfusion and diabetic CKD will be employed in both young and old animals in which multiple parameters of aging and pathology can be assayed. The impact of kidney disease will be monitored by memory and behavioral assays, total gene expression by RNAseq, targeted and untargeted assays for small molecule metabolites and several hundred lipids. Because diabetes has a significant impact on human cognition as well as kidney function, the commonalities between its influence on the brain and that of renal ischemia-reperfusion will also be determined. Genomic drift analysis, a method to assess aging based upon gene transcription, will be used to determine the physiological age and thereby the effects of kidney disease on the aging phenotype. Finally, chemical biology and transgenic tools, including an AD drug candidate developed at Salk that reduces both AD pathology and CKD, will be used to validate the interactions between kidney pathology and the aging brain. This application is in direct response to PAR-17-029 requesting multidisciplinary work to ?further our understanding of interactions between brain and non-neuronal systems in aging and AD.